Phase II Trial of Belinostat (PXD101) in Combination with Velcade

CuraGen Corporation (Nasdaq: CRGN) and TopoTarget A/S announced a Phase II clinical trial evaluating the efficacy and safety of intravenous belinostat (PXD101), a small molecule histone deacetylase (HDAC) inhibitor, in combination with Velcade(R) (bortezomib) for Injection, in multiple myeloma patients refractory to or who have rapidly relapsed from at least one previous bortezomib-containing regimen.

The Phase II clinical trial is being led by James Berenson, M.D., and will be conducted at multiple sites across the U.S. Up to 35 patients are planned for study enrollment with preliminary results anticipated by the end of 2007.

"Based on our preclinical studies that showed markedly increased anti-myeloma effects when belinostat was combined with bortezomib to treat a bortezomib-resistant myeloma in immunodeficient mice, we look forward to enrolling bortezomib-resistant multiple myeloma patients into this Phase II trial and determining whether the combination can provide clinical benefit to multiple myeloma patients that have failed, or who have relapsed on bortezomib therapy," commented Dr. Berenson. "Emerging safety results from CuraGen and NCI clinical trials that are evaluating belinostat and bortezomib have shown the combination to be generally well-tolerated. Therefore, we have initiated this Phase II study to allow relapsed and/or refractory multiple myeloma patients the ability to receive treatment with belinostat and bortezomib, and anticipate reporting preliminary results from the study by the end of the year," commented Frank Armstrong, M.D., President and Chief Executive Officer of CuraGen. " As data continues to be generated from our Phase II trials in ovarian cancer, colorectal cancer, and T-cell lymphomas, we look forward to presenting preliminary results during mid-2007, and remain on track to initiate a Phase III program during 2008 and advance belinostat towards registration."

In vitro studies published in the literature have shown that HDAC inhibitors and bortezomib, when combined, act synergistically through independent mechanisms leading to enhanced killing of cancer cells. During the 2006 ASH Annual Meeting, preclinical results evaluating belinostat in combination with bortezomib were presented in a poster entitled, "Effects of a Novel Histone Deacetylase Inhibitor, PXD101, When Used as Monotherapy or in Combination with Bortezomib on Tumor Growth in a Mouse Model of Human Multiple Myeloma." The data suggest that when mice bearing bortezomib-resistant human tumors were treated with the combination of belinostat and bortezomib, greater inhibition of both tumor growth and circulating human IgG levels were observed than when either drug was used alone, and the mice tolerated the combination well without obvious adverse effects. These results suggest that treatment with belinostat in combination with bortezomib may be an effective therapy for bortezomib-resistant multiple myeloma.

About Belinostat
Belinostat is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, including 5-FU, carboplatin, paclitaxel, cis-retinoic acid, azacitidine and Velcade(R) (bortezomib) for Injection. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents. Intravenous belinostat is currently being evaluated in multiple clinical trials as a potential treatment for multiple myeloma, T- and B-cell lymphomas, AML, mesothelioma, liver, colorectal, ovarian cancers, either alone or in combination with anti-cancer therapies. An oral formulation of belinostat is also being evaluated in a Phase I clinical trial for patients with advanced solid tumors.

Safe HarborStatements in this press release regarding management's future expectations, beliefs, intentions, goals, strategies, plans or prospects, including statements relating to the expected benefits of belinostat in combination with Velcade(R) (bortezomib) for Injection, and the potential results of the clinical trials with belinostat designed to evaluate such benefits, may constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by terminology such as "anticipate," "believe," "could," "could increase the likelihood," "estimate," "expect," "intend," "is planned," "may," "should," "will," "will enable," "would be expected," "look forward," "may provide," "would" or similar terms, variations of such terms or the negative of those terms. Such forward-looking statements involve known and unknown risks, uncertainties and other factors including the risk that any one or more of CuraGen's drug development programs will not proceed as planned for technical, scientific or commercial reasons or due to patient enrollment issues or based on new information from nonclinical or clinical studies or from other sources, the success of competing products and technologies, CuraGen's stage of development as a biopharmaceutical company, government regulation and healthcare reform, technological uncertainty and product development risks, product liability exposure, uncertainty of additional funding, CuraGen's history of incurring losses and the uncertainty of achieving profitability, reliance on research collaborations and strategic alliances, competition, patent infringement claims against CuraGen's products, processes and technologies, CuraGen's ability to protect its patents and proprietary rights and uncertainties relating to commercialization rights, as well as those risks, uncertainties and factors referred to in the Company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2006, filed with the Securities and Exchange Commission under the section "Risk Factors," as well as other documents that may be filed by CuraGen from time to time with the Securities and Exchange Commission. As a result of such risks, uncertainties and factors, the Company's actual results may differ materially from any future results, performance or achievements discussed in or implied by the forward-looking statements contained herein. CuraGen is providing the information in this press release as of this date and assumes no obligations to update the information included in this press release or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

SOURCE CuraGen Corporation

MGUS and Myeloma

U.S. medical scientists have determined immunity to cancer stem cells might help protect people with a precancerous condition from developing the disease.

Although stem cells hold great promise in the fight against certain diseases, mounting evidence suggests a tumor's growth may depend on cancer stem cells that comprise only a very small subset of the tumor.

But research by scientists at Rockefeller University suggests such cells could be an important target for cancer vaccines.

About 3 percent of adults age 40 years or more test positive for a condition known as monoclonal gammopathy of undetermined significance, or MGUS. That condition is relatively benign but in a small number of cases it progresses into multiple myeloma, a cancer of blood plasma cells.

Despite the fact MGUS and myeloma cells are genetically similar, researchers have been unable to determine why most MGUS patients never develop the cancer.

Associate Professor Madhav Dhodapkar and colleagues have determined MGUS patients who naturally develop an immune response to an embryonic stem cell protein called SOX2 appear to be protected against the development of myeloma.

The study appears in the Journal of Experimental Medicine.

Research: Two new approaches VEGF and hLL1

Two new approaches are under investigation against multiple myeloma in clinical trials at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

A Phase 2 trial with VEGF Trap will assess the drug's ability to slow tumor growth in patients with multiple myeloma. VEGF Trap is a recombinant human fusion protein that binds VEGF, a key molecule in tumor blood-vessel growth (angiogenesis).

A Phase 1 trial of hLL1 (anti-CD74), a humanized monoclonal antibody that has shown significant growth inhibition of multiple myeloma and B-lymphoma cells in preclinical studies, and whose mechanism of action is associated with inducing apoptosis (cell death), will be studied for safety and dosage.

Dr. Ruben Niesvizky, director of NewYork-Presbyterian/Weill Cornell's Multiple Myeloma Program is principal investigator of both studies.

Myeloma growth is highly dependent on VEGF (vascular endothelial growth factor) and that blood-vessel growth (angiogenesis) is a fundamental aspect of myeloma tumor growth.

VEGF Trap works by binding VEGF more tightly than the body's own receptors that mediate the angiogenic activity of VEGF.

The drug hLL1 (IMMU-115) represents the first antibody exploiting the high expression of the CD74 molecule (an invariant chain marker associated with HLA antigens) in myeloma cells. This molecule not only plays a role in immunity, but has also been shown to have direct signaling effects in hematopoietic tumors. NewYork-Presbyterian/Weill Cornell is the first to begin evaluation of this new antibody as a therapy for any disease.

The drug hLL1 is developed by Immunomedics of Morris Plains, N.J.; the company is funding the study of its drug. VEGF Trap is being developed in a collaboration between Regeneron Pharmaceuticals of Tarrytown, N.Y. and Sanofi-Aventis USA, of Bridgewater, New Jersey; the study is sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program (NCI/CTEP) under a Clinical Trials Agreement between Sanofi-Aventis and NCI; and conducted under the NCI's Division of Cancer Treatment and Diagnosis Investigational New Drug Application for VEGF Trap.

The Multiple Myeloma Program at NewYork-Presbyterian/Weill Cornell, one of the three largest such centers in the U.S., takes an aggressive and multidisciplinary approach-offering programs for transplants, vaccine development and drugs, as well as clinical research trials for all stages of the disease. The Myeloma Program is also enrolling for other investigational drug therapies.

Co-investigators for the VEGF Trap study include NewYork-Presbyterian/Weill Cornell's Drs. Jia Ruan, Roger Pearse and Morton Coleman; NewYork-Presbyterian/Columbia's Ajai Chari; and investigators representing the other members of the New York Consortium. Statistical analysis will be provided by Weill Cornell's Dr. Madhu Mazumdar. Co-investigators for the hLL1 study include Weill Cornell's Drs. Scott Ely and John Leonard.

Mayo Clinic discovers wood mold toxic to Multiple Myeloma

ROCHESTER, Minn. -- Mayo Clinic Cancer Center (http://cancercenter.mayo.edu/) researchers have found that chaetocin, a by-product of a common wood mold, has promise as a new anti-myeloma agent. Results of their study are available online in the March 15 issue of Blood (http://bloodjournal.hematologylibrary.org/).

"This research is only the beginning," says Keith Bible, M.D., Ph.D., oncologist and the study's primary investigator. "But we are very hopeful that chaetocin may some day provide needed help to our patients."

Dr. Bible's team has shown for the first time that chaetocin has promising anti-myeloma activity. They found that chaetocin's promise includes the ability to:

• Kill myeloma cells harboring a diverse array of genetic abnormalities
• Cause biological changes and induce oxidative stress in myeloma cells, leading to their death
• Selectively kill myeloma cells with superior efficacy to commonly-used anti-myeloma drugs including dexamethasone and doxorubicin
• Reduce myeloma growth in mice
• Rapidly accumulate in cancer cells

"There were a number of fascinating findings," says Crescent Isham, Mayo Graduate School student and lead author of the study. "In addition to observing many favorable aspects of chaetocin, we discovered some avenues for further research into other possible anti-myeloma agents." She says researchers were surprised that chaetocin, while structurally similar to anti-cancer agents known as histone deacetylase inhibitors (HDACIs), did not, at cytotoxic concentrations, seem to function as an HDACI; but instead that the cytotoxic mechanism appeared to be at least in part attributable to oxidative stress caused by chaetocin.

"Much more research needs to be done," says Dr. Bible. "We will continue working with chaetocin to find the best way to use it for our patients. We are also pursuing other agents which may cause similar cellular oxidative stress." It will still be a few years before patient trials can commence, he says.

Mayo Clinic has a long tradition of leadership in myeloma research and novel therapeutic development, with the oldest and largest myeloma program in the country. Dr. Bible's research is part of an ongoing initiative within Mayo's Dysproteinemia and Myeloma Groups to find promising natural or man-made agents for the treatment of myeloma and other blood diseases; and to investigate at a basic science level and subsequently translate that research into clinical practice.

Other researchers contributing to this study included Jennifer Tibodeau, Ph.D.; Wendy Jin; Ruifang Xu, M.D., Ph.D.; and Michael Timm. Funding for this research came from the National Institutes of Health and the Multiple Myeloma Research Foundation.

More information on hematology research at Mayo Clinic Cancer Center can be found on the Hematologic Malignancies Program (http://cancercenter.mayo.edu/mayo/research/hematologic_malignancies/index.cfm) Web site.

Mayo Clinic uses Measles virus to fight Multiple Myeloma

ROCHESTER, Minn. -- Mayo Clinic Cancer Center has opened a new Phase I clinical trial testing an engineered measles virus against multiple myeloma. This is the third of a series of molecular medicine studies in patients testing the potential of measles to kill cancer.

"This is the beginning of a long but exciting process," says Angela Dispenzieri, M.D., hematologist and lead researcher on the multiple myeloma clinical trial in the measles virus investigation. "We are very hopeful that this will be a step toward helping our patients."

Mayo Clinic Cancer Center is the only institution in the world currently pursuing using engineered measles viruses for cancer treatment. It has shepherded the research from basic laboratory science to therapies being tested today in several tumor types, including glioblastoma multiforme (a brain tumor), recurrent ovarian cancer and now multiple myeloma.

The measles viruses being used for these studies were constructed by inserting additional genes into the measles vaccine strain.

Many cancers, including multiple myeloma, overexpress a protein, CD46, which allows them to evade destruction by the immune system. Laboratory strains of measles virus seek out this protein and use it as a receptor by which to enter the cancer cells. Upon entry, the virus spreads, infecting nearby tumor cells and fusing them together, increasing cancer cell death.

This study differs from the other two open clinical trials because researchers are administering the measles virus strain intravenously, rather than directly to the tumor site. For multiple myeloma, the researchers are using a strain of measles virus which was engineered to carry an additional gene that codes for the sodium iodide symporter (NIS) protein.

NIS is produced by the thyroid where it attracts and concentrates iodine. This characteristic of the NIS protein can be exploited as a target in cancer therapy because it can concentrate radioactive iodine, thus providing a way to selectively irradiate cancer cells, image the tumors and monitor regression.

Eligible candidates for the multiple myeloma study will be adults with relapsed or refractory myeloma. They must not have had allogeneic stem cell transplants and must either have had a prior measles infection or been vaccinated against it.

In the 1970s, measles infections were observed to cause regression of pre-existing cancerous tumors in children. This information was noted, but nothing was done to study this phenomenon until the late 1990s, when, under the direction of Stephen Russell, M.D., Ph.D., Mayo Clinic Cancer Center's Molecular Medicine Program began investigating it. The current study and other related projects resulted.

"Mayo's multidisciplinary team and institutional support for cutting-edge research provide the perfect incubator for development of a therapeutic virus," says Dr. Russell. "We have everything we need, from basic scientists who create and test the vaccine strain to those who determine the best way to manufacture a safe biological delivery mechanism, and finally, to clinicians who understand the science and develop guidelines by which the study is conducted and correctly carried out. With this outstanding team, we can truly focus on achieving the greatest benefit for the patient."

The Mayo team using the measles virus against ovarian cancer reports early evidence of activity against the cancer, as well as demonstrated safety. The team can now move to administration of higher and potentially even more potent viral doses. The glioblastoma multiforme trial, which opened in the fall, is testing the safety of another strain of the measles virus for treatment, one that also enables biological monitoring of anti-tumor activity.

Dr. Russell's team also is looking at ways to use the measles virus to combat other cancers, including breast, pancreatic and liver cancer.

Funding for the investigation came from the National Cancer Institute, the Harold W. Siebens Foundation, and the Henry E. Asher Fund for Multiple Myeloma. Other Mayo Clinic Cancer Center researchers participating in the multiple myeloma project include Gregory Wiseman, M.D.; Val Lowe, M.D.; Morie Gertz, M.D.; David Kallmes, M.D.; and Mark Federspiel, Ph.D.

More information on measles research at Mayo Clinic can be found at the Gene and Virus Therapy Program (http://cancercenter.mayo.edu/mayo/research/gene_virus_therapy_program, link opens in new window). Potential study participants can call 507-538-7623 for more information.

Source: http://www.mayoclinic.org/news2007-rst/3954.html

New drug Enzastaurin (LY317615.HCl)

Blood, 15 February 2007, Vol. 109, No. 4, pp. 1669-1677.
Prepublished online as a Blood First Edition Paper on October 5, 2006; DOI 10.1182/blood-2006-08-042747.

Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl)

Klaus Podar¹, Marc S. Raab^1,2, Jing Zhang¹, Douglas McMillin¹, Iris Breitkreutz¹, Yu-Tzu Tai¹, Boris K. Lin³, Nikhil Munshi¹, Teru Hideshima¹, Dharminder Chauhan¹, and Kenneth C. Anderson¹

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; ² Department of Internal Medicine V, University of Heidelberg, Germany; and ³ Eli Lilly and Company, Indianapolis, IN

In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester–induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCµ. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve outcome in patients with MM.